interleukin-23-mediated signaling pathway / positive regulation of T-helper 1 type immune response / positive regulation of memory T cell differentiation / interleukin-12 receptor complex / interleukin-23 receptor complex / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / Interleukin-12 signaling / cytokine receptor activity ...interleukin-23-mediated signaling pathway / positive regulation of T-helper 1 type immune response / positive regulation of memory T cell differentiation / interleukin-12 receptor complex / interleukin-23 receptor complex / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / Interleukin-12 signaling / cytokine receptor activity / positive regulation of activated T cell proliferation / cytokine binding / positive regulation of T-helper 17 cell lineage commitment / positive regulation of defense response to virus by host / cellular response to type II interferon / cytokine-mediated signaling pathway / positive regulation of T cell mediated cytotoxicity / positive regulation of type II interferon production / receptor complex / external side of plasma membrane / signal transduction / plasma membrane 類似検索 - 分子機能
Long hematopoietin receptor, Gp130 family 2, conserved site / Long hematopoietin receptor, gp130 family signature. / : / Fibronectin type III domain / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Immunoglobulin-like fold 類似検索 - ドメイン・相同性
National Institutes of Health/National Cancer Institute (NIH/NCI)
5R01CA177684
引用
ジャーナル: Cell / 年: 2021 タイトル: Structural basis for IL-12 and IL-23 receptor sharing reveals a gateway for shaping actions on T versus NK cells. 著者: Caleb R Glassman / Yamuna Kalyani Mathiharan / Kevin M Jude / Leon Su / Ouliana Panova / Patrick J Lupardus / Jamie B Spangler / Lauren K Ely / Christoph Thomas / Georgios Skiniotis / K Christopher Garcia / 要旨: Interleukin-12 (IL-12) and IL-23 are heterodimeric cytokines that are produced by antigen-presenting cells to regulate the activation and differentiation of lymphocytes, and they share IL-12Rβ1 as a ...Interleukin-12 (IL-12) and IL-23 are heterodimeric cytokines that are produced by antigen-presenting cells to regulate the activation and differentiation of lymphocytes, and they share IL-12Rβ1 as a receptor signaling subunit. We present a crystal structure of the quaternary IL-23 (IL-23p19/p40)/IL-23R/IL-12Rβ1 complex, together with cryoelectron microscopy (cryo-EM) maps of the complete IL-12 (IL-12p35/p40)/IL-12Rβ2/IL-12Rβ1 and IL-23 receptor (IL-23R) complexes, which reveal "non-canonical" topologies where IL-12Rβ1 directly engages the common p40 subunit. We targeted the shared IL-12Rβ1/p40 interface to design a panel of IL-12 partial agonists that preserved interferon gamma (IFNγ) induction by CD8 T cells but impaired cytokine production from natural killer (NK) cells in vitro. These cell-biased properties were recapitulated in vivo, where IL-12 partial agonists elicited anti-tumor immunity to MC-38 murine adenocarcinoma absent the NK-cell-mediated toxicity seen with wild-type IL-12. Thus, the structural mechanism of receptor sharing used by IL-12 family cytokines provides a protein interface blueprint for tuning this cytokine axis for therapeutics.